1. Field of the Invention
The present invention relates to non-invasive measurement of chemical concentration within a living subject, and more particularly concerns the use of magnetic resonance to obtain such measurement.
2. Description of Related Art
Metabolite concentrations have been measured in human muscle by nuclear magnetic resonance (NMR) spectroscopy employing no spatial localization other than that provided by a surface coil. Because the sensitive volume of the surface coil often includes several different tissue or organ types, this method is unsatisfactory for measuring concentrations in a particular organ or a site of an organ of interest, such as a lesion thereon. Therefore techniques which permit localized assays are essential for the study of metabolic variations in normal and disease (suspected or real) states.
For example, there is evidence that the high-energy phosphate metabolite, adenosine triphosphate (ATP), responsible for muscular contraction among other things in the heart, is reduced in myocardial infarction. It is postulated that differences in the absolute myocardial ATP concentration, and stress-induced changes in the myocardial phospho-creatine (PCr)/ATP ratio may permit the determination of the relative amounts of salvageable and non-salvageable myocardium in subjects, patients, with ischemic heart disease.
The measurement of concentration by magnetic resonance (MR) requires three basic elements: (i) the measurement of a signal that is proportional to a concentration, (ii) the determination of the volume or mass of tissue contributing the signal, and (iii) the determination of the constants of proportionality.
To date, the measurement of concentrations with one dimensional (1D) localized surface coil spectroscopy has either not been possible or is unreliable because of the difficulty in performing item (ii) above. With 1-D MR spectroscopic localization, the volume or mass of tissue in the volume element (voxel) cannot easily be measured by MRI because of the diffuse sensitivity profile of the surface coil which delimits the other two dimensions. For example in myocardial infarction, one group of researchers report in one study of a significant negative correlation between the myocardial ATP level localized by 1D MR spectroscopy and the extent of the infarction measured by radionuclide imaging, but then in a second study, no significant correlation between ATP and infarction size. The latter results are contrary to expectations since dead cells do not contain ATP. Clearly at issue is whether tissue volume or tissue phosphate concentrations are changing. Proper account must therefore be taken of the tissue volumes involved.
U.S. Pat. No. 4,881,032 "Method of, and Apparatus For, NMR Spectroscopic Metabolite Imaging and Quantification by P. A. Bottomley, P. B. Roeruer, W. A. Edelstein, 0. M. Mueller, issued Nov. 14, 1989 describes a method of measuring concentrations employing 3D resolved spectroscopy The method employs 3D chemical shift imaging (CSI), with a concentration reference located in a different volume element (voxel) than that being assayed to link MR response signal strength to concentration, and MR Imaging (MRI) to determine the tissue volume in the voxel being assayed.
This method has several drawbacks in practical implementation in cardiac patients:
1. Even with 3-D CSI localization, measuring tissue volumes is often difficult when the anatomical structure varies on a finer scale than the typical spectroscopy voxel of 10-30 ml, such as occurs when measuring phosphate concentrations in the heart. Proton (.sup.1 H) imaging has much greater resolution and sensitivity than NMR spectroscopy of nuclei such as phosphorus (.sup.31 P). PA1 2. It is not easy to account for "voxel bleed" effects in CSI because the extent of the "bleed" artifact depends critically on the distribution of the anatomy relative to the CSI spatial sampling grid. The bleed can lead to significant over-and under-estimation of signals, and hence errors in estimating tissue concentrations in individual voxels. This can be overcome, at least partially, by averaging values from several voxels, but this would be undesirable if knowledge of the spatial variation in concentrations were important (e.g.., in myocardial infarction). Potential errors from the "bleed" artifact are worse when the concentration reference and the metabolite being assayed are in voxels at different locations. PA1 3. There are other possible non-physiological reasons why signal from tissue volume quantified by MRI doesn't contribute to its full extent to a localized spectrum. Dephasing of signals across a voxel could result from inhomogeneity in the main magnetic field, or from phase variations between the transmitted field and the detection field when separate transmit and receive coils are used. PA1 4. To measure concentrations, a concentration reference is required. When the location of the reference differs from that of the voxel where concentrations are being assayed, proper account must be taken of the differences in the transmitted and received fields at the 2 locations.
It is desirable to measure human metabolite concentrations as expeditiously as possible. For example, the measurement of ATP concentrations for evaluating heart damage should be completed in as short a time as possible in order to be tolerated by a sick patient. For the detection of ischemia via the observation of transient reductions in PCr, the patient must perform a stress test during imaging to cause metabolism of PCr. Since 3D imaging takes a longer time than 1D or 2D imaging, the patient can exercise for a shorter period of time to acquire an NMR data set. Some patients cannot tolerate a prolonged stress test.
Currently, there is a need for a system which provides a quick, non-invasive, accurate method of measuring metabolites in subjects.